Pub Date : 2024-10-28DOI: 10.1016/j.ijpharm.2024.124883
Daniel Tristan Osanlóo , Denny Mahlin , Simon Bjerregaard , Björn Bergenståhl , Anna Millqvist-Fureby
This article compares and explores vacuum foam-drying as an alternative drying technology to freeze-drying and spray drying for a recombinant human lipase as the model protein. Materials characteristics such as structure, surface composition and the solid-state properties of the dry materials were compared and investigated. Moreover, the technical functionality in terms of reconstitution characteristics and the lipase stability were also investigated. The stability of the lipase was evaluated through activity measurements. Sucrose and dextran D40 (40 kDa) were used as matrix former and the surfactant α-dodecyl maltoside was used as surface active additive. The study demonstrated that the drying technique greatly influenced the material structure and composition which in turn affected the reconstitution characteristics. The lipase was overrepresented at the material surface in declining order spray-dried > vacuum foam-dried > freeze-dried. The lipase activity was retained up to 10 % lipase content in solids, but at 20 % lipase a loss of activity was observed for all drying techniques. Phase separation in the solid material may be an explanation. Vacuum foam-drying shows promise as an alternative drying technique for the lipase, and potentially other proteins.
{"title":"Exploring vacuum foam drying as an alternative to freeze-drying and spray drying for a human lipase","authors":"Daniel Tristan Osanlóo , Denny Mahlin , Simon Bjerregaard , Björn Bergenståhl , Anna Millqvist-Fureby","doi":"10.1016/j.ijpharm.2024.124883","DOIUrl":"10.1016/j.ijpharm.2024.124883","url":null,"abstract":"<div><div>This article compares and explores vacuum foam-drying as an alternative drying technology to freeze-drying and spray drying for a recombinant human lipase as the model protein. Materials characteristics such as structure, surface composition and the solid-state properties of the dry materials were compared and investigated. Moreover, the technical functionality in terms of reconstitution characteristics and the lipase stability were also investigated. The stability of the lipase was evaluated through activity measurements. Sucrose and dextran D40 (40 kDa) were used as matrix former and the surfactant α-dodecyl maltoside was used as surface active additive. The study demonstrated that the drying technique greatly influenced the material structure and composition which in turn affected the reconstitution characteristics. The lipase was overrepresented at the material surface in declining order spray-dried > vacuum foam-dried > freeze-dried. The lipase activity was retained up to 10 % lipase content in solids, but at 20 % lipase a loss of activity was observed for all drying techniques. Phase separation in the solid material may be an explanation. Vacuum foam-drying shows promise as an alternative drying technique for the lipase, and potentially other proteins.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":"667 ","pages":"Article 124883"},"PeriodicalIF":5.3,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142560748","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
This research focuses on exploring the solid solubility and miscibility of Etoricoxib, a poorly water-soluble anti-inflammatory drug, within Soluplus®, a polymer used as a matrix for 3D-printed tablets. By utilizing hot-melt extrusion (HME), the drug was dispersed within Soluplus® to enhance its solubility. The extrudates were then employed in 3D printing to create customized solid oral dosage form. This study’s novelty lies in combining HME and 3D printing, aiming to improve drug incorporation, stability, and effectiveness in the final formulation. Comprehensive characterization techniques, including hot stage microscopy (HSM), scanning electron microscopy (SEM), micro-computed tomography (Micro-CT), florescence microscopy, optical microscopy, X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), solubility studies, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and aqueous solubility study were utilized to elucidate the physicochemical properties, thermal stability, and structural integrity for the extruded filaments (the printing ink), and 3D printed tablets made thereof. Furthermore, the in vitro drug release profile of the 3D printed tablet was systematically evaluated, revealing a controlled drug release pattern from the finished dosage form. The systematic investigation reported herein, starting from theoretical miscibility to the printing ink development through HME, detailed characterization of the extruded filaments, and further solid oral formulation development by additive manufacturing can be utilized as a platform technology or a pathway for the development of personalized medicine with drugs having similar physicochemical properties.
这项研究的重点是探索水溶性较差的抗炎药物 Etoricoxib 在 Soluplus® （一种用作 3D 打印片剂基质的聚合物）中的固溶性和混溶性。通过热熔挤出（HME），药物被分散在 Soluplus® 中，以提高其溶解度。然后将挤出物用于三维打印，制成定制的固体口服剂型。这项研究的新颖之处在于将 HME 和 3D 打印技术相结合，旨在提高药物在最终制剂中的掺入度、稳定性和有效性。综合表征技术包括热台显微镜（HSM）、扫描电子显微镜（SEM）、显微计算机断层扫描（Micro-CT）、荧光显微镜、光学显微镜、X 射线衍射（XRD）、傅立叶变换红外光谱（FT-IR）、溶解度研究、利用差示扫描量热法（DSC）、热重分析法（TGA）和水溶性研究，阐明了挤出长丝（印刷油墨）及其制成的 3D 打印药片的理化性质、热稳定性和结构完整性。此外，还对 3D 打印片剂的体外药物释放曲线进行了系统评估，揭示了成品剂型的控释模式。本文所报告的系统性研究，从理论上的混溶性开始，到通过 HME 开发印刷油墨、详细表征挤压丝，以及通过增材制造进一步开发固体口服制剂，可作为一种平台技术或途径，用于开发具有类似理化性质的药物的个性化药物。
{"title":"Leveraging solid solubility and miscibility of etoricoxib in Soluplus® towards manufacturing of 3D printed etoricoxib tablets by additive manufacturing","authors":"Makka Krupali Ashokbhai , Shubham Ghatole , Ujjwal Gupta , Lohare Rahul Sanjay , Subhadeep Roy , Velayutham Ravichandiran , Santanu Kaity","doi":"10.1016/j.ijpharm.2024.124881","DOIUrl":"10.1016/j.ijpharm.2024.124881","url":null,"abstract":"<div><div>This research focuses on exploring the solid solubility and miscibility of Etoricoxib, a poorly water-soluble anti-inflammatory drug, within Soluplus®, a polymer used as a matrix for 3D-printed tablets. By utilizing hot-melt extrusion (HME), the drug was dispersed within Soluplus® to enhance its solubility. The extrudates were then employed in 3D printing to create customized solid oral dosage form. This study’s novelty lies in combining HME and 3D printing, aiming to improve drug incorporation, stability, and effectiveness in the final formulation. Comprehensive characterization techniques, including hot stage microscopy (HSM), scanning electron microscopy (SEM), micro-computed tomography (Micro-CT), florescence microscopy, optical microscopy, X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), solubility studies, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and aqueous solubility study were utilized to elucidate the physicochemical properties, thermal stability, and structural integrity for the extruded filaments (the printing ink), and 3D printed tablets made thereof. Furthermore, the in vitro drug release profile of the 3D printed tablet was systematically evaluated, revealing a controlled drug release pattern from the finished dosage form. The systematic investigation reported herein, starting from theoretical miscibility to the printing ink development through HME, detailed characterization of the extruded filaments, and further solid oral formulation development by additive manufacturing can be utilized as a platform technology or a pathway for the development of personalized medicine with drugs having similar physicochemical properties.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":"667 ","pages":"Article 124881"},"PeriodicalIF":5.3,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142566491","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-28DOI: 10.1016/j.ijpharm.2024.124872
Lina Vargas Michelena , Giselle R. Bedogni , Miguel O. Jara , Robert O. Williams III , Claudio J. Salomon
Fenbendazole is a broad-spectrum anthelmintic used in veterinary medicine. It is a lipophilic benzimidazole derivative with low water solubility (<0.1 g/L) recently studied for repositioning in cancer treatment. These potential new uses highlight the need for new dosage forms. Thus, chitosan-crosslinked microparticles were prepared by spray drying, applying a Design of Experiments approach to optimize the composition of the microparticles, evaluating the type and mass of chitosan and crosslinking agent, alongside crosslinking reaction time. The recovered optimized microparticles were characterized by infrared spectroscopy, and changes in the drug crystalline phase were studied by differential scanning calorimetry and X-ray powder diffraction, further confirmed by wide-angle X-ray scattering. After encapsulation of fenbendazole in the chitosan-crosslinked matrix, the resulting microparticles had a particle size of 2.43 μm with a polydispersion index of 0.754 and a Zeta potential value of + 49.85 mV. In vitro dissolution showed that the optimized microparticles had an improved dissolution profile compared to the non-encapsulated drug. The analysis of the encapsulated drug in the solid state showed a remarkable reduction of its crystalline properties. In conclusion, these results demonstrate that fenbendazole encapsulation into an optimized chitosan-crosslinked matrix leads to better biopharmaceutical performance.
{"title":"Formulation and optimization of chitosan-based amorphous fenbendazole microparticles through a design of experiment approach","authors":"Lina Vargas Michelena , Giselle R. Bedogni , Miguel O. Jara , Robert O. Williams III , Claudio J. Salomon","doi":"10.1016/j.ijpharm.2024.124872","DOIUrl":"10.1016/j.ijpharm.2024.124872","url":null,"abstract":"<div><div>Fenbendazole is a broad-spectrum anthelmintic used in veterinary medicine. It is a lipophilic benzimidazole derivative with low water solubility (<0.1 g/L) recently studied for repositioning in cancer treatment. These potential new uses highlight the need for new dosage forms. Thus, chitosan-crosslinked microparticles were prepared by spray drying, applying a Design of Experiments approach to optimize the composition of the microparticles, evaluating the type and mass of chitosan and crosslinking agent, alongside crosslinking reaction time. The recovered optimized microparticles were characterized by infrared spectroscopy, and changes in the drug crystalline phase were studied by differential scanning calorimetry and X-ray powder diffraction, further confirmed by wide-angle X-ray scattering. After encapsulation of fenbendazole in the chitosan-crosslinked matrix, the resulting microparticles had a particle size of 2.43 μm with a polydispersion index of 0.754 and a Zeta potential value of + 49.85 mV. <em>In vitro</em> dissolution showed that the optimized microparticles had an improved dissolution profile compared to the non-encapsulated drug. The analysis of the encapsulated drug in the solid state showed a remarkable reduction of its crystalline properties. In conclusion, these results demonstrate that fenbendazole encapsulation into an optimized chitosan-crosslinked matrix leads to better biopharmaceutical performance.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":"667 ","pages":"Article 124872"},"PeriodicalIF":5.3,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142567125","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-28DOI: 10.1016/j.ijpharm.2024.124852
Runqiao Dong , Daniel J. Goodwin , Joelle Nassar , Ranjit Dhenge , Sofia S.H. Matrali , Neil Hodnett , J. Axel Zeitler
Roller compaction is a crucial unit operation in pharmaceutical manufacturing, with its ribbon porosity widely recognised as a critical quality attribute. Terahertz spectroscopy has emerged as a fast and non-destructive technique to measure porosity in pharmaceutical products. From a sensing perspective, the irregular shape and uneven surface of fragmented ribbon pieces can affect the accuracy and precision of the measurements, particularly for techniques that probe only a small sampling volume. It is known that the porosity is not uniform within the ribbon structure, with variations expected across the width of the ribbon and in the microstructure corresponding to its surface texture. However, typical pharmaceutical analysis methods, such as envelope density, only report an average bulk porosity, are slow to operate and limited in accuracy. To address this challenge, we developed and trained convolutional neural network models using THz spectra as input to classify four types of topography typically encountered in ribbons: ridge, valley, flat plane and edge points. The classifiers achieved 91% validation accuracy in both identifying outliers and differentiating between ribbons of smooth and knurled surfaces. For the more challenging task of distinguishing between the ridges and valleys of knurled surfaces, an 81% testing accuracy was achieved. Once each measurement is paired with its topography, resolving the density distribution within the sample is possible. This data can be combined to arrive at an average bulk porosity value compatible with conventional pharmaceutical analysis.
{"title":"Roller compaction: Measuring ribbon porosity by terahertz spectroscopy and machine learning","authors":"Runqiao Dong , Daniel J. Goodwin , Joelle Nassar , Ranjit Dhenge , Sofia S.H. Matrali , Neil Hodnett , J. Axel Zeitler","doi":"10.1016/j.ijpharm.2024.124852","DOIUrl":"10.1016/j.ijpharm.2024.124852","url":null,"abstract":"<div><div>Roller compaction is a crucial unit operation in pharmaceutical manufacturing, with its ribbon porosity widely recognised as a critical quality attribute. Terahertz spectroscopy has emerged as a fast and non-destructive technique to measure porosity in pharmaceutical products. From a sensing perspective, the irregular shape and uneven surface of fragmented ribbon pieces can affect the accuracy and precision of the measurements, particularly for techniques that probe only a small sampling volume. It is known that the porosity is not uniform within the ribbon structure, with variations expected across the width of the ribbon and in the microstructure corresponding to its surface texture. However, typical pharmaceutical analysis methods, such as envelope density, only report an average bulk porosity, are slow to operate and limited in accuracy. To address this challenge, we developed and trained convolutional neural network models using THz spectra as input to classify four types of topography typically encountered in ribbons: ridge, valley, flat plane and edge points. The classifiers achieved 91% validation accuracy in both identifying outliers and differentiating between ribbons of smooth and knurled surfaces. For the more challenging task of distinguishing between the ridges and valleys of knurled surfaces, an 81% testing accuracy was achieved. Once each measurement is paired with its topography, resolving the density distribution within the sample is possible. This data can be combined to arrive at an average bulk porosity value compatible with conventional pharmaceutical analysis.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":"667 ","pages":"Article 124852"},"PeriodicalIF":5.3,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142566967","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-28DOI: 10.1016/j.ijpharm.2024.124876
Katarzyna Reczyńska-Kolman , Dorota Ochońska , Monika Brzychczy-Włoch , Elżbieta Pamuła
Solid lipid nanoparticles are currently one of the most widely investigated types of drug delivery carriers. Considering the fact that their clinical translation boosted after the approval of two COVID-19 mRNA vaccines, it is crucial to fully explain how the processing parameters affect the properties of the obtained nanoparticles and the drug loading efficiency. This study aimed to evaluate the influence of different manufacturing parameters on the properties of stearic acid-based nanoparticles fabricated using the emulsification/solvent diffusion method. It was found that the type of organic solvent used has a major effect on the morphology of the nanoparticles, with chloroform being suitable for the production of spherical nanoparticles. The size and polydispersity of the nanoparticles were affected by the concentration of surfactant in the external aqueous phase, the concentration of stearic acid in the organic phase, and the homogenization amplitude. The optimized nanoparticles were successfully loaded with an antibacterial peptide – LL-37. The presence of LL-37 did not significantly influence nanoparticle morphology or cytocompatibility. The obtained nanoparticles showed antibacterial activity against the reference strain of Streptococcus pyogenes (ATCC 12384). The developed solid lipid nanoparticles are promising drug carries that can be further optimized for the treatment of infected wounds or bacterial infections in the respiratory system.
{"title":"Stearic acid-based nanoparticles loaded with antibacterial peptides – Bacitracin and LL-37: Selection of manufacturing parameters, cytocompatibility, and antibacterial efficacy","authors":"Katarzyna Reczyńska-Kolman , Dorota Ochońska , Monika Brzychczy-Włoch , Elżbieta Pamuła","doi":"10.1016/j.ijpharm.2024.124876","DOIUrl":"10.1016/j.ijpharm.2024.124876","url":null,"abstract":"<div><div>Solid lipid nanoparticles are currently one of the most widely investigated types of drug delivery carriers. Considering the fact that their clinical translation boosted after the approval of two COVID-19 mRNA vaccines, it is crucial to fully explain how the processing parameters affect the properties of the obtained nanoparticles and the drug loading efficiency. This study aimed to evaluate the influence of different manufacturing parameters on the properties of stearic acid-based nanoparticles fabricated using the emulsification/solvent diffusion method. It was found that the type of organic solvent used has a major effect on the morphology of the nanoparticles, with chloroform being suitable for the production of spherical nanoparticles. The size and polydispersity of the nanoparticles were affected by the concentration of surfactant in the external aqueous phase, the concentration of stearic acid in the organic phase, and the homogenization amplitude. The optimized nanoparticles were successfully loaded with an antibacterial peptide – LL-37. The presence of LL-37 did not significantly influence nanoparticle morphology or cytocompatibility. The obtained nanoparticles showed antibacterial activity against the reference strain of <em>Streptococcus pyogenes</em> (ATCC 12384)<em>.</em> The developed solid lipid nanoparticles are promising drug carries that can be further optimized for the treatment of infected wounds or bacterial infections in the respiratory system.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":"667 ","pages":"Article 124876"},"PeriodicalIF":5.3,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142545404","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-28DOI: 10.1016/j.ijpharm.2024.124887
James William McKeage , Andrew Zheng Hao Tan , Andrew James Taberner
Subcutaneous (SC) drug delivery offers several advantages over intravenous (IV) delivery including: self-administration, improved patient experience, and reduced treatment costs. Unfortunately, each SC delivery is currently limited to ∼ 2.25 mL with IV administration required when the delivery volume exceeds this value. In this work, we explore a new technique for large volume subcutaneous drug delivery that uses microneedles to break through the epidermis then forms the liquid drug into many small jets that penetrate past the ends of the microneedles and into the subcutaneous (or muscle) tissue. By performing multiple simultaneous injections, this delivery approach avoids the volume limitations of SC delivery, and thus may be able to greatly increase the volume we can deliver to this space. Here, we present a novel multi-jet prototype that forms seven simultaneous jets through 30G needles that have been shortened to have an exposed length of just ∼ 1 mm. The jet speed, shape, and volume of jets formed through these microneedles are measured to assess the consistency of jet production through the microneedles. We then perform jet injections of volumes up to 3.9 mL into ex vivo porcine tissue. The results demonstrate the successful delivery (>95 %) of 3.9 mL in just 0.3 s using jet injection performed through microneedles. This volume is almost double the maximum volume of current autoinjectors and the perceived limit for subcutaneous injection (2.25 mL). We also find that jet speeds of 70 m/s and below do not achieve complete delivery of 3.9 mL with our prototype system, and that the addition of microneedles leads to more consistent large volume delivery than equivalent needle-free injections. These results demonstrate the promise of multi-jet injection through microneedles to accommodate volumes much greater than current autoinjectors, and thus potentially allow patient self-administration in many more delivery applications.
{"title":"Jet injection through microneedles for large volume subcutaneous delivery","authors":"James William McKeage , Andrew Zheng Hao Tan , Andrew James Taberner","doi":"10.1016/j.ijpharm.2024.124887","DOIUrl":"10.1016/j.ijpharm.2024.124887","url":null,"abstract":"<div><div>Subcutaneous (SC) drug delivery offers several advantages over intravenous (IV) delivery including: self-administration, improved patient experience, and reduced treatment costs. Unfortunately, each SC delivery is currently limited to ∼ 2.25 mL with IV administration required when the delivery volume exceeds this value. In this work, we explore a new technique for large volume subcutaneous drug delivery that uses microneedles to break through the epidermis then forms the liquid drug into many small jets that penetrate past the ends of the microneedles and into the subcutaneous (or muscle) tissue. By performing multiple simultaneous injections, this delivery approach avoids the volume limitations of SC delivery, and thus may be able to greatly increase the volume we can deliver to this space. Here, we present a novel multi-jet prototype that forms seven simultaneous jets through 30G needles that have been shortened to have an exposed length of just ∼ 1<!--> <!-->mm. The jet speed, shape, and volume of jets formed through these microneedles are measured to assess the consistency of jet production through the microneedles. We then perform jet injections of volumes up to 3.9 mL into ex vivo porcine tissue. The results demonstrate the successful delivery (>95 %) of 3.9 mL in just 0.3 s using jet injection performed through microneedles. This volume is almost double the maximum volume of current autoinjectors and the perceived limit for subcutaneous injection (2.25 mL). We also find that jet speeds of 70 m/s and below do not achieve complete delivery of 3.9 mL with our prototype system, and that the addition of microneedles leads to more consistent large volume delivery than equivalent needle-free injections. These results demonstrate the promise of multi-jet injection through microneedles to accommodate volumes much greater than current autoinjectors, and thus potentially allow patient self-administration in many more delivery applications.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":"667 ","pages":"Article 124887"},"PeriodicalIF":5.3,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142545401","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-28DOI: 10.1016/j.ijpharm.2024.124879
Charan M Gowda, Sarika Wairkar
The proposed study aimed to develop a topical gel containing azelaic acid (AZA)-based lyotropic liquid crystals (LLCs) for the treatment of acne vulgaris. AZA-based LLCs were optimized by varying Poloxamer-407 and polyvinyl alcohol concentration using a central composite design, which showed that both independent variables had a significant effect on the formulation. The highest desirable trial of AZA-based LLCs (Batch-7) containing 300 mg poloxamer-407 and 100 mg polyvinyl alcohol depicted the particle size, zeta potential, and entrapment efficiency of 184.2 nm, −16.1 mV, and 79.96 %, respectively. TEM images confirmed the globular vesicles of LLCs, and ATR-FTIR and DSC results confirmed the compatibility of formulation excipients. In vitro, the release of AZA, AZA-based LLCs, AZA-based LLC gel, and marketed gel showed a release of 23.29, 95.24, 91.07 and 59.88 %, respectively, after 24 h in phosphate buffer pH 6.8. Ex vivo release of AZA-based LLC gel displayed an 86.56 % release after 24 h. The antimicrobial activity of AZA-based LLC gel exhibited a comparable efficacy with marketed gel against Cutibacterium acnes, Staphylococcus epidermis and Staphylococcus aureus. The acute dermal irritation study indicated excellent safety and skin compatibility of AZA-based LLC gel without any erythema and edema. The dermatopharmacokinetic study displayed an enhanced drug retention for AZA-based LLC gel (146.121 ± 21.13 µg/cm2) than marketed gel (58.58 ± 15.95 µg/cm2) in the dermal layer, which would improve its therapeutic effect. These outcomes proved that AZA-based LLC gel has the potential to enhance skin penetration and retention for effective management of acne vulgaris.
{"title":"Azelaic acid-based lyotropic liquid crystals gel for acne vulgaris: Formulation optimization, antimicrobial activity and dermatopharmacokinetic study","authors":"Charan M Gowda, Sarika Wairkar","doi":"10.1016/j.ijpharm.2024.124879","DOIUrl":"10.1016/j.ijpharm.2024.124879","url":null,"abstract":"<div><div>The proposed study aimed to develop a topical gel containing azelaic acid (AZA)-based lyotropic liquid crystals (LLCs) for the treatment of acne vulgaris. AZA-based LLCs were optimized by varying Poloxamer-407 and polyvinyl alcohol concentration using a central composite design, which showed that both independent variables had a significant effect on the formulation. The highest desirable trial of AZA-based LLCs (Batch-7) containing 300 mg poloxamer-407 and 100 mg polyvinyl alcohol depicted the particle size, zeta potential, and entrapment efficiency of 184.2 nm, −16.1 mV, and 79.96 %, respectively. TEM images confirmed the globular vesicles of LLCs, and ATR-FTIR and DSC results confirmed the compatibility of formulation excipients. In vitro, the release of AZA, AZA-based LLCs, AZA-based LLC gel, and marketed gel showed a release of 23.29, 95.24, 91.07 and 59.88 %, respectively, after 24 h in phosphate buffer pH 6.8. <em>Ex vivo</em> release of AZA-based LLC gel displayed an 86.56 % release after 24 h. The antimicrobial activity of AZA-based LLC gel exhibited a comparable efficacy with marketed gel against <em>Cutibacterium acnes, Staphylococcus epidermis</em> and <em>Staphylococcus aureus</em>. The acute dermal irritation study indicated excellent safety and skin compatibility of AZA-based LLC gel without any erythema and edema. The dermatopharmacokinetic study displayed an enhanced drug retention for AZA-based LLC gel (146.121 ± 21.13 µg/cm<sup>2</sup>) than marketed gel (58.58 ± 15.95 µg/cm<sup>2</sup>) in the dermal layer, which would improve its therapeutic effect. These outcomes proved that AZA-based LLC gel has the potential to enhance skin penetration and retention for effective management of acne vulgaris.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":"667 ","pages":"Article 124879"},"PeriodicalIF":5.3,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142568838","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Wound healing is a complex biological process crucial for tissue repair, especially in chronic wounds where healing is impaired. Liposomes have emerged as promising vehicles for delivering therapeutics to facilitate wound repair. Liposomes have been explored as effective carriers for therapeutic agents. However, traditional methods of liposome preparation face significant challenges, particularly in achieving consistent stability and precise control over drug encapsulation and release. This study addresses these challenges by pioneering the development of Hybrid Liposomes (HLPs) using microfluidic technology, which provides more controlled characteristics through precisely managed formulation parameters. Notably, the formation of Polydopamine (PDA) polymer within HLPs facilitates pH-responsive drug release, making them well-suited for acidic wound environments. Furthermore, surface modification with Folic Acid (FA) enhances cellular interaction with the HLPs. In vitro and in vivo studies demonstrate the efficacy of HLPs loaded with Hyaluronic Acid (HA) or Phenytoin (PHT) in promoting wound healing. Microfluidics optimizes the stability of HLPs over 90 days, underscoring their potential as a potent, antibiotic-free drug delivery system. In conclusion, this research advances the understanding of microfluidic optimization for HLPs, offering cutting-edge drug delivery systems. The transformative potential of targeted HLPs through microfluidics holds promise for revolutionizing wound healing and inspires optimism for effective therapeutic interventions.
{"title":"Novel microfluidic development of pH-responsive hybrid liposomes: In vitro and in vivo assessment for enhanced wound Healing","authors":"Hakam Alaqabani , Alaa Hammad , Yara Abosnwber , Yvonne Perrie","doi":"10.1016/j.ijpharm.2024.124884","DOIUrl":"10.1016/j.ijpharm.2024.124884","url":null,"abstract":"<div><div>Wound healing is a complex biological process crucial for tissue repair, especially in chronic wounds where healing is impaired. Liposomes have emerged as promising vehicles for delivering therapeutics to facilitate wound repair. Liposomes have been explored as effective carriers for therapeutic agents. However, traditional methods of liposome preparation face significant challenges, particularly in achieving consistent stability and precise control over drug encapsulation and release. This study addresses these challenges by pioneering the development of Hybrid Liposomes (HLPs) using microfluidic technology, which provides more controlled characteristics through precisely managed formulation parameters. Notably, the formation of Polydopamine (PDA) polymer within HLPs facilitates pH-responsive drug release, making them well-suited for acidic wound environments. Furthermore, surface modification with Folic Acid (FA) enhances cellular interaction with the HLPs. <em>In vitro</em> and <em>in vivo</em> studies demonstrate the efficacy of HLPs loaded with Hyaluronic Acid (HA) or Phenytoin (PHT) in promoting wound healing. Microfluidics optimizes the stability of HLPs over 90 days, underscoring their potential as a potent, antibiotic-free drug delivery system. In conclusion, this research advances the understanding of microfluidic optimization for HLPs, offering cutting-edge drug delivery systems. The transformative potential of targeted HLPs through microfluidics holds promise for revolutionizing wound healing and inspires optimism for effective therapeutic interventions.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":"667 ","pages":"Article 124884"},"PeriodicalIF":5.3,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142545402","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Monoclonal antibodies (mAbs) are an evolving class of biopharmaceuticals, with advancements evident across various stages of their development. While discovery, mAb chemical optimization, production and purification processes have been thoroughly reviewed, this paper aims to offer a summary of novel strategies in administration of mAbs. At present, systemic delivery of mAbs is available through parenteral administration routes with focus on subcutaneous administration. In addition, oriented toward patient-friendly therapy, other less invasive administration routes of mAbs, such as inhalation, nasal, transdermal, and oral administration, are explored. Literature data reveals the potential for local delivery of mAbs via inhalation, nasal, transdermal, intratumoral, intravitreal and vaginal administration, offering high efficacy with fewer systemic adverse effects. However, to date, only mAb medicines are available for intravitreal administration, mainly due to higher bioavailability, and an intranasal spray is authorised as a medical device. The review highlights the promising data in approval of novel administration routes, likely through inhalation, but further intensive research considering the current obstacles, is essential.
单克隆抗体（mAbs）是一类不断发展的生物制药，在其发展的各个阶段都取得了明显的进步。本文旨在总结 mAbs 给药方面的新策略。目前，mAb 可通过肠外给药途径进行全身给药，重点是皮下给药。此外，为了方便患者治疗，还探索了其他侵入性较小的 mAbs 给药途径，如吸入、鼻腔、透皮和口服给药。文献数据显示，通过吸入、鼻腔、透皮、瘤内、玻璃体内和阴道给药等途径局部给药的 mAbs 具有较高的疗效和较少的全身不良反应。然而，到目前为止，只有用于玻璃体内给药的 mAb 药物，这主要是由于生物利用度较高，而鼻内喷雾剂已被批准为医疗器械。本综述强调了在批准新型给药途径（可能是通过吸入）方面的有希望的数据，但考虑到目前存在的障碍，进一步的深入研究是必不可少的。
{"title":"Novel strategies in systemic and local administration of therapeutic monoclonal antibodies","authors":"Monika Prašnikar, Maja Bjelošević Žiberna, Mirjam Gosenca Matjaž, Pegi Ahlin Grabnar","doi":"10.1016/j.ijpharm.2024.124877","DOIUrl":"10.1016/j.ijpharm.2024.124877","url":null,"abstract":"<div><div>Monoclonal antibodies (mAbs) are an evolving class of biopharmaceuticals, with advancements evident across various stages of their development. While discovery, mAb chemical optimization, production and purification processes have been thoroughly reviewed, this paper aims to offer a summary of novel strategies in administration of mAbs. At present, systemic delivery of mAbs is available through parenteral administration routes with focus on subcutaneous administration. In addition, oriented toward patient-friendly therapy, other less invasive administration routes of mAbs, such as inhalation, nasal, transdermal, and oral administration, are explored. Literature data reveals the potential for local delivery of mAbs via inhalation, nasal, transdermal, intratumoral, intravitreal and vaginal administration, offering high efficacy with fewer systemic adverse effects. However, to date, only mAb medicines are available for intravitreal administration, mainly due to higher bioavailability, and an intranasal spray is authorised as a medical device. The review highlights the promising data in approval of novel administration routes, likely through inhalation, but further intensive research considering the current obstacles, is essential.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":"667 ","pages":"Article 124877"},"PeriodicalIF":5.3,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142566494","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Even though the spring and parachute approach for poorly water-soluble drug candidates effectively improves their dissolution curves with eutectic mixtures, deep eutectic solvents, solid dispersion polymers, and solid solutions, we cannot consider that its enabling factor in these pharmaceutical modifications was enough to be clarified. Based on our previous study that oxybuprocaine acts as a role of parachute generator for piroxicam, the present study explored a small-molecule parachute generator and found that propranolol, a β-adrenergic-blocking drug, has a parachute effect on the supersaturated state of piroxicam. In addition, changing the concentration of tetracaine and dibucaine to 10 mM and 2.5 mM also showed a parachute effect. These parachute generators control piroxicam’s dissolved state kinetically by making the supersaturated state of piroxicam a steady state. However, as the piroxicam anhydrous crystals diminished and the piroxicam monohydrate crystals grew due to Ostwald ripening, it led to attenuating the supersaturated state. This finding advances the elucidation of the mechanism of the parachute effect of polymers.
{"title":"Spring and parachute approach for piroxicam dissolution; its phenomenological model on the thermodynamics of irreversible processes","authors":"Momoko Fujita , Tomohiro Tsuchida , Hikaru Kataoka, Chihiro Tsunoda, Kota Moritake, Satoru Goto","doi":"10.1016/j.ijpharm.2024.124886","DOIUrl":"10.1016/j.ijpharm.2024.124886","url":null,"abstract":"<div><div>Even though the <em>spring</em> and <em>parachute</em> approach for poorly water-soluble drug candidates effectively improves their dissolution curves with eutectic mixtures, deep eutectic solvents, solid dispersion polymers, and solid solutions, we cannot consider that its enabling factor in these pharmaceutical modifications was enough to be clarified. Based on our previous study that oxybuprocaine acts as a role of <em>parachute</em> generator for piroxicam, the present study explored a small-molecule <em>parachute</em> generator and found that propranolol, a β-adrenergic-blocking drug, has a <em>parachute</em> effect on the supersaturated state of piroxicam. In addition, changing the concentration of tetracaine and dibucaine to 10 mM and 2.5 mM also showed a <em>parachute</em> effect. These <em>parachute</em> generators control piroxicam’s dissolved state kinetically by making the supersaturated state of piroxicam a steady state. However, as the piroxicam anhydrous crystals diminished and the piroxicam monohydrate crystals grew due to Ostwald ripening, it led to attenuating the supersaturated state. This finding advances the elucidation of the mechanism of the <em>parachute</em> effect of polymers.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":"667 ","pages":"Article 124886"},"PeriodicalIF":5.3,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142545403","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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